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1
Signaling through dynamic linkers as revealed by PKA.通过 PKA 揭示的通过动态连接子的信号转导
Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14231-6. doi: 10.1073/pnas.1312644110. Epub 2013 Aug 14.
2
Assembly of allosteric macromolecular switches: lessons from PKA.别构大分子开关的组装：PKA 的启示。
Nat Rev Mol Cell Biol. 2012 Oct;13(10):646-58. doi: 10.1038/nrm3432. Epub 2012 Sep 20.
3
Localization and quaternary structure of the PKA RIβ holoenzyme.PKA RIβ 全酶的定位和四级结构。
Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12443-8. doi: 10.1073/pnas.1209538109. Epub 2012 Jul 13.
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Structure and allostery of the PKA RIIβ tetrameric holoenzyme.PKA RIIβ 四聚体全酶的结构与别构调控。
Science. 2012 Feb 10;335(6069):712-6. doi: 10.1126/science.1213979.
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Realizing the allosteric potential of the tetrameric protein kinase A RIα holoenzyme.揭示四聚体蛋白激酶 A RIα 全酶的别构潜能。
Structure. 2011 Feb 9;19(2):265-76. doi: 10.1016/j.str.2010.12.005.
6
Cyclic AMP analog blocks kinase activation by stabilizing inactive conformation: conformational selection highlights a new concept in allosteric inhibitor design.环腺苷酸类似物通过稳定无活性构象来阻断激酶的激活：构象选择突出了变构抑制剂设计中的新概念。
Mol Cell Proteomics. 2011 Mar;10(3):M110.004390. doi: 10.1074/mcp.M110.004390. Epub 2010 Nov 16.
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Phosphodiesterases catalyze hydrolysis of cAMP-bound to regulatory subunit of protein kinase A and mediate signal termination.磷酸二酯酶催化 cAMP 与蛋白激酶 A 的调节亚基结合的水解，并介导信号终止。
Mol Cell Proteomics. 2011 Feb;10(2):M110.002295. doi: 10.1074/mcp.M110.002295. Epub 2010 Oct 5.
8
Allosteric communication between cAMP binding sites in the RI subunit of protein kinase A revealed by NMR.通过 NMR 揭示蛋白激酶 A 的 RI 亚基中环腺苷酸结合位点之间的变构通讯。
J Biol Chem. 2010 Apr 30;285(18):14062-70. doi: 10.1074/jbc.M110.106666. Epub 2010 Mar 2.
9
Sensing domain dynamics in protein kinase A-I{alpha} complexes by solution X-ray scattering.通过溶液 X 射线散射探测蛋白激酶 A-I{alpha}复合物中的感应结构域动力学。
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Virtual Cell modelling and simulation software environment.虚拟细胞建模与仿真软件环境。
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利用马尔可夫状态模型深入理解蛋白激酶A调节亚基RIα对环磷酸腺苷（cAMP）结合的激活机制。

Using Markov state models to develop a mechanistic understanding of protein kinase A regulatory subunit RIα activation in response to cAMP binding.

作者信息

Boras Britton W, Kornev Alexandr, Taylor Susan S, McCulloch Andrew D

机构信息

From the Departments of Bioengineering.

Chemistry and Biochemistry.

出版信息

J Biol Chem. 2014 Oct 24;289(43):30040-51. doi: 10.1074/jbc.M114.568907. Epub 2014 Sep 8.

DOI:10.1074/jbc.M114.568907
PMID:25202018
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4208011/
Abstract

Protein kinase A (PKA) holoenzyme consists of two catalytic (C) subunits and a regulatory (R) subunit dimer (R(2)C(2)). The kinase is activated by the binding of cAMPs to the two cyclic nucleotide binding domains (CBDs), A and B, on each R-subunit. Despite extensive study, details of the allosteric mechanisms underlying the cooperativity of holoenzyme activation remain unclear. Several Markov state models of PKA-RIα were developed to test competing theories of activation for the R(2)C(2) complex. We found that CBD-B plays an essential role in R-C interaction and promotes the release of the first C-subunit prior to the binding to CBD-A. This favors a conformational selection mechanism for release of the first C-subunit of PKA. However, the release of the second C-subunit requires all four cAMP sites to be occupied. These analyses elucidate R-C heterodimer interactions in the cooperative activation of PKA and cAMP binding and represent a new mechanistic model of R(2)C(2) PKA-RIα activation.

摘要

蛋白激酶A（PKA）全酶由两个催化（C）亚基和一个调节（R）亚基二聚体（R₂C₂）组成。激酶通过cAMP与每个R亚基上的两个环核苷酸结合结构域（CBD）A和B结合而被激活。尽管进行了广泛研究，但全酶激活协同性背后的变构机制细节仍不清楚。开发了几种PKA-RIα的马尔可夫状态模型来测试R₂C₂复合物激活的竞争理论。我们发现CBD-B在R-C相互作用中起关键作用，并促进第一个C亚基在与CBD-A结合之前的释放。这有利于PKA第一个C亚基释放的构象选择机制。然而，第二个C亚基的释放需要所有四个cAMP位点都被占据。这些分析阐明了PKA协同激活过程中R-C异二聚体相互作用以及cAMP结合情况，并代表了R₂C₂ PKA-RIα激活的一种新机制模型。